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Requirement for glycogen synthase kinase-3β in cell survival and NF-κB activation

Abstract

Glycogen synthase kinase-3 (GSK-3)-α and -β are closely related protein-serine kinases, which act as inhibitory components of Wnt signalling during embryonic development and cell proliferation in adult tissues1,2. Insight into the physiological function of GSK-3 has emerged from genetic analysis in Drosophila3,4, Dictyostelium 5 and yeast6,7. Here we show that disruption of the murine GSK-3β gene results in embryonic lethality caused by severe liver degeneration during mid-gestation, a phenotype consistent with excessive tumour necrosis factor (TNF) toxicity, as observed in mice lacking genes involved in the activation of the transcription factor activation NF-κB. GSK-3β-deficient embryos were rescued by inhibition of TNF using an anti-TNF-α antibody. Fibroblasts from GSK-3β-deficient embryos were hypersensitive to TNF-α and showed reduced NF-κB function. Lithium treatment (which inhibits GSK-3; refs 8, 9) sensitized wild-type fibroblasts to TNF and inhibited transactivation of NF-κB. The early steps leading to NF-κB activation (degradation of I-κB and translocation of NF-κB to the nucleus) were unaffected by the loss of GSK-3β, indicating that NF-κB is regulated by GSK-3β at the level of the transcriptional complex. Thus, GSK-3β facilitates NF-κB function.

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Figure 1: Targeted disruption of the GSK-3β locus.
Figure 2: Phenotype of GSK-3β-/- embryos.
Figure 3: GSK-3β-deficient cells show increased sensitivity to TNF-induced apoptosis.
Figure 4: Apoptotic sensitivity of GSK-3β-/- fibroblasts.
Figure 5: Inhibition of GSK-3β reduces TNF-inducible NF-κB activation.

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Acknowledgements

We thank W.-C. Yeh for the TRAF2-deficient mouse EFs and C. Mirtsos, M. Bonnard, T. Nicklee, A. Ali, M. Parsons, T. Mak, D. Wakeham and A. Shahinian for technical help and advice. K.P.H. is supported by a Medical Research Council of Canada Studentship. J.R.W. is supported by grants from the Medical Research Council and Howard Hughes Medical Institute and is a Medical Research Council Senior Scientist.

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Correspondence to James R. Woodgett.

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Hoeflich, K., Luo, J., Rubie, E. et al. Requirement for glycogen synthase kinase-3β in cell survival and NF-κB activation. Nature 406, 86–90 (2000). https://doi.org/10.1038/35017574

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